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Hydrogen sulfide (H2S)—a potent gaseous signaling molecule—has emerged as a critical regulator of cardiovascular homeostasis. H2S is produced enzymatically by 3 constitutively active endogenous enzymes in all mammalian species. Within the past 2 decades, studies administering H2S-donating agents and the genetic manipulation of H2S-producing enzymes have revealed multiple beneficial effects of H2S, including vasodilation, activation of antiapoptotic and antioxidant pathways, and anti-inflammatory effects. More recently, the heightened enthusiasm in this field has shifted to the development of novel H2S-donating agents that exert favorable pharmacological profiles. This has led to the discovery of novel H2S-mediated signaling pathways. This review will discuss recently developed H2S therapeutics, introduce signaling pathways that are influenced by H2S-dependent sulfhydration, and explore the dual-protective effect of H2S in cardiorenal syndrome.